Classical Hodgkin lymphoma (cHL) is the most common form of lymphoma affecting people under the age of 30 in the Western World. Treatment responses after initial therapies are excellent in young people, however late effects cause considerable mortality and morbidity. 25- 30% of patients experience relapse or progressive disease following initial treatment and 5-15% die of their disease within 10 years. An improved understanding of the pathobiology of cHL is an essential requirement for biomarker development and novel therapeutic approaches to improve initial and late outcomes. cHL is unique among cancers in that the malignant cells comprise less than 1% of the tumor with the remainder of the tumor microenvironment (TME) composed of a variety of immune cells. We have shown that in some populations, the composition of the TME affects cHL outcome. Here we will examine the correlation between the TME composition and survival in cHL across, age, sex, EBV status, histology and racial/ethnic groups (Aim 1). We will also examine the effect of host factors (age, sex, race/ethnicity, SES), EBV status and histology on TME composition (Aim 2) and we will conduct analyses to determine whether TME mediates or interacts with host factors to impact survival (Aim 3). This will be the largest study of cHL TME conducted to date and the only one designed to specifically examine relationships in different racial/ethnic and age groups. To conduct this study, we have assembled a multidisciplinary team of experts. We will perform gene expression profiling (our validated Scott Predictor) using NanoString and we will examine specific T-cell and other subsets, including macrophages and B-cells, implicated in outcome, using immunohistochemistry on formalin-fixed paraffin-embedded diagnostic biopsies from 2,688 U.S. multiethnic cHL patients from 5 large clinical centers. EBV DNA in the tumor cells will also be measured. Tissue microarrays will be constructed and immunohistochemistry automatically scored. We will also collect demographic and clinical data including age, race/ethnicity, sex, socioeconomic status, treatment, progression-free and overall survival, B symptoms, anatomic site, stage and other information. With this sample size, the minimum detectable Hazard Ratio (HR) with 80% power is 1.55 to 1.32 for a TME binary variable with frequency ranging from 0.1 to 0.5, respectively. The ranges of detectable marginal HR are well-within the range of previously observed effects and should enable us to test marginal effects by race/ethnicity, age and other factors. The significance of this proposal lies in identifying population differences for a cutting-edge clinical biomarker and elucidating the immunobiology of the TME in different demographic groups.